Coronary atherosclerosis is the major cause of death in women in the USA. While coronary artery bypass surgery decreases symptomatic and clinical evidence of cardiac ischemia it does not alter the underlying process. Patients may develop recurrent symptoms due to saphenous vein graft occlusion, graft atherosclerosis, or progression of underlying coronary disease. Interventions that reduce the rate of coronary atherosclerosis progression would significantly benefit women following bypass surgery and possibly benefit all women with atherosclerotic disease. Some observational studies suggest that postmenopausal estrogen replacement therapy reduces cardiac morbidity by up to 50%. The benefit of estrogen and progestin therapy (HRT) in women with established coronary disease has not been studied. The efficacy of HRT to delay the development of saphenous graft atherosclerosis is unknown. This randomized, double-masked, placebo- controlled trial tests the hypothesis that HRT started shortly after coronary bypass surgery will delay the development of graft atherosclerosis and reduce the occurrence of graft occlusion. Women will be randomized to placebo or HRT with 17b-estradiol plus medroxyprogesterone acetate (or 17 -estradiol if post hysterectomy) within 4 months of surgery. The development of vein graft atherosclerosis will be measured using quantitative coronary angiographic and intravascular ultrasound assessment of disease severity and extent. Studies will be performed 6 months and 3.5 years after randomization. We shall determine the influence of HRT on the primary outcome variables of the change in severity and extent of atherosclerosis in vein grafts over 3.5 years of therapy. We postulate that the pathophysiologic mechanisms of platelet activation, fibrinogen binding to platelets, vascular reactivity, coagulation and fibrinolytic factors and lipoprotein composition predict the occurrence of graft occlusion and graft atherosclerosis. The effect of HRT on these factors will be measured. The proposal also tests the hypothesis that HRT exerts its beneficial effects by its effects on these risk factors in addition to more traditional risk factors including lipids and lipoprotein profile. The influence of these risk factors and the effect of HRT on the frequency of early graft closure (identified on a 6 month coronary angiogram) will be assessed.